Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sister chromatid separation depends on the release of cohesion by the activity of Esp1, a member of the caspase family [1, 2]. In budding yeast, Esp1p is kept inactive by its association with Pds1p, until the onset of anaphase, when Pds1p is ubiquitinated by the APC/Cdc20 complex [3--5] and subsequently degraded by the 26S proteasome. Pds1 is not an essential gene in budding yeast, but is required for cell cycle arrest prior to anaphase in response to the disruption of spindle structures [6, 7]. Thus, Pds1 mutant yeast cells display precocious sister chromatid separation in the presence of nocodazole [6]. Mammalian orthologs of yeast Esp1 and Pds1, separin and securin, have been identified [8], and, as anticipated, a nondegradable mutant form of securin inhibits sister separation when added to mitotic Xenopus egg extracts [8]. Securin was also independently identified as PTTG (pituitary tumor transforming gene), a gene overexpressed in pituitary tumors [9]. The relationship between its overexpression in tumors and its control of sister chromatid cohesion remains ill defined. To explore securin function in mammals, we took a targeted gene disruption approach in mice. Here, we report that securin is neither essential for cell viability nor required for spindle checkpoint function, and mice lacking securin are viable and apparently normal, but mouse embryonic fibroblasts lacking securin grow abnormally in culture.
...
PMID:Securin is not required for cellular viability, but is required for normal growth of mouse embryonic fibroblasts. 1151 52

Cell cycle progression is controlled at several different junctures by the targeted destruction of cell cycle regulatory proteins. These carefully orchestrated events include the destruction of the securin protein to permit entry into anaphase, and the destruction of cyclin B to permit exit from mitosis. These destruction events are mediated by the ubiquitin/proteasome system. The human ubiquitin-conjugating enzyme, UbcH10, is an essential mediator of the mitotic destruction events. We report here the 1.95-A crystal structure of a mutant UbcH10, in which the active site cysteine has been replaced with a serine. Functional analysis indicates that the mutant is active in accepting ubiquitin, although not as efficiently as wild-type. Examination of the crystal structure reveals that the NH2-terminal extension in UbcH10 is disordered and that a conserved 3(10)-helix places a lysine residue near the active site. Analysis of relevant mutants demonstrates that for ubiquitin-adduct formation the presence or absence of the NH2-terminal extension has little effect, whereas the lysine residue near the active site has significant effect. The structure provides additional insight into UbcH10 function including possible sites of interaction with the anaphase promoting complex/cyclosome and the disposition of a putative destruction box motif in the structure.
...
PMID:Structural and functional analysis of the human mitotic-specific ubiquitin-conjugating enzyme, UbcH10. 1192 73

Key events in mitosis such as sister chromatid separation and subsequent inactivation of cyclin-dependent kinase 1 are regulated by ubiquitin-dependent proteolysis. These events are mediated by the anaphase-promoting complex (APC), a cell cycle-regulated ubiquitin ligase that assembles multiubiquitin chains on regulatory proteins such as securin and cyclins and thereby targets them for destruction by the 26S proteasome.
...
PMID:The anaphase-promoting complex: proteolysis in mitosis and beyond. 1204 31

The proteins securin and cyclin B are destroyed in mitosis by the ubiquitin/proteasome system. This destruction is important to mitotic progression. The N-terminal regions of these proteins contain the sequence features recognized by the ubiquitination system. We have demonstrated using circular dichroism and 1-D and 2-D nuclear magnetic resonance that these rather substantial regions are natively unfolded. Based on these findings, we propose a model that helps to explain previously enigmatic observations.
...
PMID:The regions of securin and cyclin B proteins recognized by the ubiquitination machinery are natively unfolded. 1222 Jun 79

Yin6 is a yeast homolog of Int6, which is implicated in tumorigenesis. We show that Yin6 binds to and regulates proteasome activity. Overexpression of Yin6 strengthens proteasome function while inactivation weakens and causes the accumulation of polyubiquitinated proteins including securin/Cut2 and cyclin/Cdc13. Yin6 regulates the proteasome by preferentially interacting with Rpn5, a conserved proteasome subunit, and affecting its localization/assembly. We showed previously that Yin6 cooperates with Ras1 to mediate chromosome segregation; here, we demonstrate that Ras1 similarly regulates the proteasome via Rpn5. In yeast, human Int6 binds Rpn5 and regulates its localization. We propose that human Int6, either alone or cooperatively with Ras, influences proteasome activities via Rpn5. Inactivating Int6 can lead to accumulation of mitotic regulators affecting cell division and mitotic fidelity.
...
PMID:Schizosaccharomyces pombe Int6 and Ras homologs regulate cell division and mitotic fidelity via the proteasome. 1255 9

Proper function of the 26 S proteasome requires assembly of the regulatory complex, which is composed of the lid and base subcomplexes. We characterized Rpn5, a lid subunit, in fission yeast. We show that Rpn5 associates with the proteasome rpn5. Deletion (rpn5Delta) exacerbates the growth defects in proteasome mutants, leading to mitotic abnormalities, which correlate with accumulation of polyubiquitinated proteins, such as Cut2/securin. Rpn5 expression is tightly controlled; both overexpression and deletion of rpn5 impair proteasome functions. The proteasome is assembled around the inner nuclear membrane in wild-type cells; however, in rpn5Delta cells, proteasome subunits are improperly assembled and/or localized. In the lid mutants, Rpn5 is mislocalized in the cytosol, while in the base mutants, Rpn5 can enter the nucleus, but is left in the nucleoplasm, and not assembled into the nuclear membrane. These results suggest that Rpn5 is a dosage-dependent proteasome regulator and plays a role in mediating proper proteasome assembly. Moreover, the Rpn5 assembly may be a cooperative process that involves at least two steps: 1) nuclear import and 2) subsequent assembly into the nuclear membrane. The former step requires other components of the lid, while the latter requires the base. Human Rpn5 rescues the phenotypes associated with rpn5Delta and is incorporated into the yeast proteasome, suggesting that Rpn5 functions are highly conserved.
...
PMID:Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly. 1278 82

Faithful segregation of homologous chromosomes during the first meiotic division is essential for further embryo development. The question at issue is whether the same mechanisms ensuring correct separation of sister chromatids in mitosis are at work during the first meiotic division. In mitosis, sister chromatids are linked by a cohesin complex holding them together until their disjunction at anaphase. Their disjunction is mediated by Separase, which cleaves the cohesin. The activation of Separase requires prior degradation of its associated inhibitor, called securin. Securin is a target of the APC/C (Anaphase Promoting Complex/Cyclosome), a cell cycle-regulated ubiquitin ligase that ubiquitinates securin at the metaphase-to-anaphase transition and thereby targets it for degradation by the 26S proteasome. After securin degradation, Separase cleaves the cohesins and triggers chromatid separation, a prerequisite for anaphase. In yeast and worms, the segregation of homologous chromosomes in meiosis I depends on the APC/C and Separase activity. Yet, it is unclear if Separase is required for the first meiotic division in vertebrates because APC/C activity is thought to be dispensable in frog oocytes. We therefore investigated if Separase activity is required for correct chromosome segregation in meiosis I in mouse oocytes.
...
PMID:The meiosis I-to-meiosis II transition in mouse oocytes requires separase activity. 1456 5

All eukaryotic cells possess elaborate mechanisms to protect genome integrity and ensure survival after DNA damage, ceasing proliferation and granting time for DNA repair. Securin is an inhibitory protein that is bound to a protease called Separase to inhibit sister chromatid separation until the onset of anaphase. At the metaphase-to-anaphase transition, Securin is degraded by the anaphase-promoting complex or cyclosome, and Separase contributes to the release of cohesins from the chromosome, allowing for the segregation of sister chromatids to opposite spindle poles. Here we provide evidence that human Securin (hSecurin) has a novel role in cell cycle arrest after exposure to UV light or ionizing radiation. In fact, irradiation downregulated the level of hSecurin protein, accelerating its degradation via the proteasome and reducing hSecurin mRNA translation, but the presence of hSecurin is necessary for cell proliferation arrest following UV treatment. Moreover, an alteration of UV-induced hSecurin downregulation could lead directly to the accumulation of DNA damage and the subsequent development of malignant tumors.
...
PMID:Securin is a target of the UV response pathway in mammalian cells. 1502 62

The cell cycle is the process by which cells grow, replicate their genome and divide. The cell cycle control system is a cyclically-operating biochemical device constructed from a set of interacting proteins that induce and coordinate proper progression through the cycle, and includes cyclins, cyclin-dependent kinases (CDK) and their inhibitors (CDKI). There are mainly two families of CDKI, the INK family (INK4a/p16; INK4b/p15; INK4c/p18 and INK4d/p19) and the WAF/KIP family (WAF1/p21; KIP1/p27; KIP2/p57). Progression through the cell cycle is mainly dependent on fluctuations in the concentration of cyclins and CDKI achieved through the programmed degradation of these proteins by proteolysis within the ubiquitin-proteasome system. There is also a transcriptional regulation of cyclin expression, probably dependent on CDK phosphorylation. The p53 family--p53, p63 and p73--function as transcription factors that play a major role in regulating the response of mammalian cells to stressors and damage, in part through the transcriptional activation of genes involved in cell cycle control (e.g. p21), DNA repair, senescence, angiogenesis and apoptosis. Essential for the maintenance of euploidy during mitosis is human securin, identical to the product of the pituitary tumour-transforming gene (PTTG). Loss of regulation at the G1/S transition appears to be a common event among virtually all types of human tumours. Aberrations of one or more components of the pRb/p16/cyclin D1/CDK4 pathway seem to be a frequent event (80%) in pituitary tumours. The role of p27 is rather that of a haploinsufficient gene. p27-/- mice show an increased growth rate, due to increased cellularity, testicular and ovarian cell hyperplasia and infertility, and hyperplasia of the pituitary intermediate lobe with nearly 100% mortality caused by such a benign pituitary tumour. Although the p27 gene was not found to be mutated in human pituitary tumours and its mRNA expression was similar in tumour samples in comparison with normal pituitaries, the load of p27 protein expression in corticotroph adenomas and pituitary carcinomas was shown to be much lower than those in normal pituitary tissue or other types of pituitary adenoma, suggesting that post-translational processing of p27 accelerates its removal from the nucleus. In respect to p27 degradation and its cellular compartmentalization, several pathways have been explored. Malignant tumours are associated with increased nuclear immunostaining for Jun-activation binding protein-1 (Jab1) which is responsible for phosphorylated p27 export from the nucleus. Corticotrophinomas are characterized by massively increased phosphorylation of p27 on Thr187, but are not associated with changes in Jab1. Macrophage inhibitory factor (MIF), which binds and inactivates Jab1, was noted to be over-expressed in tumours with abundant Jab1, suggesting that it may be part of a compensatory mechanism to moderate Jab1 activity. Proteasomal degradation of p27 requires its ubiquitylation by the SCF ubiquitin ligase, with specific addressing by the F-box protein Skp2 and its co-factor Cks1. Pituitary tumours with high p27 protein expression showed significantly less Skp2 expression than samples with low p27 immunostaining, suggesting that increased Skp2 could play at least a part in this process. No difference was observed in Cks1 mRNA levels between normal pituitaries and pituitary adenomas. The present data suggest that inhibition of growth and tumour development is sensitive not only to the absolute levels of p27 protein, but also to its cellular compartmentalization. Very recent findings from our group have established up-regulation of the serine-threonine kinase Akt in pituitary tumours compared to normal pituitary, which may cause phosphorylation of p27 on Thr157 and cytoplasmic retention of p27. PTTG protein is highly expressed in various human tumours, including pituitary tumours. While its mRNA levels are low in normal pituitary, increases in PTTG transcripts from more than 50% to more than 10-fold were recorded in the majority of a series of pituitary adenomas. Control of the cell cycle is a vital part of the cell's replication machinery. Disruption of this process is commonly seen in pituitary tumours and we are now beginning to identify regulatory elements which are likely to play a major role in pituitary oncogenesis.
...
PMID:Cell cycle dysregulation in pituitary oncogenesis. 1528 39

The anaphase-promoting complex or cyclosome (APC/C) is a multiprotein subunit E3 ubiquitin ligase complex that controls segregation of chromosomes and exit from mitosis in eukaryotes. It triggers elimination of key cell cycle regulators such as securin and mitotic cyclins during mitosis by polyubiquitinating them for proteasome degradation. Seven core subunit homologs of APC/C (APC1, APC2, APC11, CDC16, CDC23, CDC27, and DOC1) were identified in the Trypanosoma brucei genome data base. Expression of six of them was individually ablated by RNA interference in both the procyclic and bloodstream forms of T. brucei. Only the CDC27- and APC1-depleted cells were enriched in the G2/M phase with inhibited growth. Further studies indicated that T. brucei APC1 and CDC27 failed to complement the corresponding deletion mutants of budding yeast. However, their depletion from procyclic-form T. brucei enriched cells with two kinetoplasts and an enlarged nucleus possessing short metaphase-like mitotic spindles, suggesting that APC1 and CDC27 may play essential roles in promoting anaphase in the procyclic form. Their depletion from the bloodstream form, however, enriched cells with two kinetoplasts and two nuclei connected through a microtubule bundle, suggesting a late anaphase arrest. This is the first time functional APC/C subunit homologs were identified in T. brucei. The apparent differential activities of this putative APC/C in two distinct developmental stages suggest an unusual function. The apparent lack of functional involvement of some of the other individual structural subunit homologs of APC/C may indicate the structural uniqueness of T. brucei APC/C.
...
PMID:Depletion of anaphase-promoting complex or cyclosome (APC/C) subunit homolog APC1 or CDC27 of Trypanosoma brucei arrests the procyclic form in metaphase but the bloodstream form in anaphase. 1599 9


1 2 3 Next >>

---